Functional characterizations of the androgen receptor confirm that the molecular basis of androgen action is transcriptional regulation.
In an effort to understand the molecular basis of androgen action in the prostate, we isolated androgen receptor (AR) cDNA from rat ventral prostate cells and analyzed the transcriptional regulatory activity of the encoded protein in a cotransfection assay. We found that AR is capable of inducing chloramphenicol acetyltransferase activity more than 20-fold using the mouse mammary tumor virus LTR as a source of androgen response elements. This induction was observed in both monkey CV1 cells and human HeLa cells, neither of which contains endogenous functional AR, and was entirely dependent on added androgens. Deletion mapping studies showed that carboxy-terminal deletions of approximately 250 amino acids convert AR into a constitutive activator of transcription. In addition, a chimeric receptor protein containing the amino-terminus and DNA-binding domains of AR fused to the previously defined ligand domain of the glucocorticoid receptor was found to be fully functional based on dexamethasone-induced chloramphenicol acetyltransferase activity. Our results support the prediction that androgens modulate rates of transcriptional initiation, suggesting that posttranscriptional effects of androgens are secondary responses. Moreover, these data reveal that, like other steroid receptors, AR contains a number of distinct regulatory regions important for normal activity. The isolation and characterization of fully functional AR sequences will facilitate the use of molecular genetics to study complex androgen responses in target tissues such as the prostate.
Rundlett
S E
SE
Department of Molecular Biology, University of Arizona, Tucson 85721.
Wu
X P
XP
Miesfeld
R L
RL
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D004247:DNA / Q000235:genetics; D008297:Male; D008967:Molecular Biology; D009154:Mutation; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D000728:Androgens; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D004247:DNA